N-demethylation of opiate derivatives is a necessary chemical step in the preparation of “NaI” products, including naltrexone and naloxone. All of the “NaI” compounds are prepared from nor-opiates (opiates contained an NH group) and are derived from natural opiates or their derivatives that have been N-demethylated. Therefore the conversion of an N-methyl functional group into an N-alkyl functional group via an NH functional group is an important transformation process in the production of opiates.
One of the current processes for the N-demethylation of an opiate containing a ketone group is to convert the opiate into an alkyloxy- or aryloxy-carbonyl opiate, followed by its hydrolysis to form a nor-opiate. For example, oxycodone is converted into ethoxycarbonyl-noroxycodone, and the subsequent hydrolysis of ethoxycarbonyl-noroxycodone with either a strong acid or a strong base forms noroxycodone. However, the transformation is accompanied with the formation of aldol dimer impurities that are extremely difficult to remove from the desired product. Thus, there is a need for improved processes for the N-demethylation of opiates comprising ketone groups such that the formation of aldol dimer impurities is minimized or eliminated.